WO2012066565A2 - Maléate d'asénapine amorphe et forme cristalline et procédé pour leur préparation - Google Patents
Maléate d'asénapine amorphe et forme cristalline et procédé pour leur préparation Download PDFInfo
- Publication number
- WO2012066565A2 WO2012066565A2 PCT/IN2011/000783 IN2011000783W WO2012066565A2 WO 2012066565 A2 WO2012066565 A2 WO 2012066565A2 IN 2011000783 W IN2011000783 W IN 2011000783W WO 2012066565 A2 WO2012066565 A2 WO 2012066565A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- asenapine maleate
- asenapine
- microns
- particle size
- maleate
- Prior art date
Links
- GMDCDXMAFMEDAG-CHHFXETESA-N (S,S)-asenapine maleate Chemical compound OC(=O)\C=C/C(O)=O.O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 GMDCDXMAFMEDAG-CHHFXETESA-N 0.000 title claims abstract description 128
- 229960001615 asenapine maleate Drugs 0.000 title claims abstract description 127
- 238000000034 method Methods 0.000 title claims description 43
- 238000002360 preparation method Methods 0.000 title description 13
- 239000002245 particle Substances 0.000 claims abstract description 43
- 239000002904 solvent Substances 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- VSWBSWWIRNCQIJ-HUUCEWRRSA-N (S,S)-asenapine Chemical compound O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-HUUCEWRRSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229960005245 asenapine Drugs 0.000 claims description 12
- -1 alkyl acetates Chemical class 0.000 claims description 11
- 238000003801 milling Methods 0.000 claims description 11
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 10
- 238000007873 sieving Methods 0.000 claims description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 150000002576 ketones Chemical class 0.000 claims description 9
- 239000002002 slurry Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 238000001694 spray drying Methods 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 7
- 150000002170 ethers Chemical class 0.000 claims description 7
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000000227 grinding Methods 0.000 claims description 6
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 5
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 claims description 4
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 239000012296 anti-solvent Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000010409 thin film Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims 1
- 101150035600 atpD gene Proteins 0.000 claims 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 26
- 238000001035 drying Methods 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000000376 reactant Substances 0.000 description 6
- 238000010902 jet-milling Methods 0.000 description 5
- 239000007788 liquid Chemical group 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000020925 Bipolar disease Diseases 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VSWBSWWIRNCQIJ-GJZGRUSLSA-N (R,R)-asenapine Chemical compound O1C2=CC=CC=C2[C@@H]2CN(C)C[C@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-GJZGRUSLSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 101100136727 Caenorhabditis elegans psd-1 gene Proteins 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
Definitions
- the invention encompasses monoclinic form of asenapine maleate having particle size in terms of d95 is less than about 100 microns.
- the present invention provides microcrystalline monoclinic form of asenapine maleate having particle size in terms of d95 is less than about 10 microns and process for preparing and pharmaceutical composition of it.
- the present invention also relates to amorphous asenapine maleate, process for preparing it and pharmaceutical composition thereof.
- Asenapine Maleate which is the generic name for the compound of formula (I), trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro- l H-dibenz[2,3:6,7] oxepine[4,5- cjpyrrole Maleic acid salt, is an antipsychotic drug used for treatment for schizo hrenia.
- U.S Patent No. 4, 145,434 discloses asenapine and its process for preparation. Asenapine is developed as Maleate salt.
- U.S Patent No. 7,73 1 ,458 discloses crystalline asenapine maleate salt in the orthorhombic form. It also discloses process for preparation of crystall ine asenapine maleate in monoclinic form.
- PCT publication no. 95/23600 A l discloses pharmaceutical composition for sublingual or buccal administration of asenapine maleate.
- US patent application Pub. No. 20080090892 Al discloses asenapine and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein the compound is at least 50% amorphous based on total weight of the compound.
- Other important properties relate to the ease of processing the form into pharmaceutical dosages, as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet.
- An aspect of the present invention is to provide substantially pure monoclinic form of asenapine maleate and process for preparation thereof.
- Another general aspect of the present invention is to provide substantially pure monoclinic form of asenapine maleate having d95 particle size of less than about 100 microns.
- Another general aspect of the present invention provides process for preparing substantially pure monoclinic form of asenapine maleate having d95 particle size of less than about 100 microns.
- the present invention provides a process for controlling the particle size of substantially pure monoclinic form having d95 particle size of less than about 100 microns.
- An another aspect of the present invention is to provide substantially pure microcrystalline monoclinic form of asenapine maleate having d95 particle size of less than about 10 microns
- Another aspect of the present invention also relates to amorphous form of Asenapine Maleate and process for preparation thereof.
- FIG. 1 is a characteristic powder X-ray powder diffraction (XRPD) pattern of amorphous Asenapine Maleate.
- FIG. 2 is the characteristic particle size distribution (PSD) of substantially pure monoclinic form of Asenapine Maleate wherein d95 is less than about 30 microns obtained by sieving through 200 mesh.
- PSD characteristic particle size distribution
- FIG. 3 is the characteristic particle size distribution (PSD) of substantially pure monoclinic form of Asenapine Maleate wherein d95 is less than about 10 microns obtained by micronization after sieving of 200 mesh.
- PSD characteristic particle size distribution
- the present invention provides substantially pure monoclinic form of Asenapine Maleate of formula (I)
- the 'substantially pure' monoclinic form of asenapine maleate is having polymorphic purity of at least 99.99% of monoclinic form or which contains preferably less than about 1 % of orthorhombic form, more preferably 0.05% of orthorhombic form and most preferably no detectable amount of orthorhombic form of asenapine maleate or free from orthorhombic form of asenapine maleate.
- the slurry of asenapine maleate may be obtained by dissolving asenapine maleate in one or more suitable organic solvents comprises of C 3- 6 ketones or a mixture thereof with water, N-methylpyrrolidone, C 3- 6 amides, halo-substituted C 6 -i2 aromatic hydrocarbons propylene glycol, dimethyl sulfoxide, dimethyl carbonate, CM alkyl alcohols, a mixture of a C
- suitable organic solvents comprises of C 3- 6 ketones or a mixture thereof with water, N-methylpyrrolidone, C 3- 6 amides, halo-substituted C 6 -i2 aromatic hydrocarbons propylene glycol, dimethyl s
- the asenapine maleate used as the starting material may be monoclinic form of having polymorphic purity of 99% to 99.5%.
- the embodiments of the process may include heating the slurry of the step (i) to obtain reaction mass followed by cooling.
- the reaction mass may be heated upto temperature of 40 to 60°C and the cooling at about 5°C to 10°C.
- the reaction mass may be stirred for 30 minutes to 2 hours.
- the substantially pure monoclinic form of asenapine maleate may be isolated by filtration, or removal of solvent under vaccum, drying under vaccum or any other techniques known in the art.
- the particle size of the drug substance influences biopharmaceutical properties of the drug product.
- the particle size of the drug substance affects drug product manufacturing and dissolution and hence its bioavailability.
- the particle size in terms of d95, is particularly less than about 100 microns, more particularly less than about 50 microns and most particularly less than about 30 microns.
- d95 means that 95% of the particles (based on volume) are smaller than or equal to the indicated size.
- the present invention provides substantially pure monoclinic form of asenapine maleate that is microcrystalline.
- microcrystalline means that the form comprises particles having a size distribution characterized by a d95 of less than 10 microns, particularly less than 7 microns.
- the invention provides a process for controlling the particle size of substantially pure monoclinic form of asenapine maleate
- step (b) isolating asenapine maleate having D95 particle size of less than about 30 microns; c) milling asenapine maleate obtained in step (b); and d) isolating substantially pure monoclinic form of asenapine maleate particles having D95 particle size of less than about 10 microns.
- step (a) the sieving of asenapine maleate in step (a) is performed through 200 mesh.
- the sieving of asenapine maleate in step (a) through 200 mesh results in substantially pure monoclinic form of asenapine maleate having D95 particle size of less than about 30 microns in single stroke.
- micronization step (c) is performed to further reduce the particle size to microcrystalline asenapine maleate comprises of jet milling performed with feeding pressure of about 3 kg and grinding pressure of about 4 kg.
- the jet milling cycle may vary from 1 to 5 cycles to obtain (D95) less than about 10 microns.
- the jet milling cycle may vary from 1 to 5 cycles to obtain (D95) less than about 10 microns.
- the invention provides a process for preparing substantially pure microcrystalline monoclinic form of asenapine maleate comprising the steps of;
- the miling in step (a) is performed to reduce the particle size to microcrystalline level and to achieve microcrystalline Asenapine Maleate.
- the milling step is performed with feeding pressure of about 3 kg and grinding pressure of about 4 kg.
- the milling cycles may vary from 1 to 5 cycles to obtain (D95) less than about 10 microns.
- the slurry of micronized asenapine maleate may be obtained by dissolving asenapine maleate in one or more suitable organic solvents.
- micronized asenapine maleate when used as the starting material may be monoclinic form of asenapine maleate having polymorphic purity of 99% to 99.5%.
- the solvent for step (a) for preparing slurry of microcrystalline asenapine maleate comprises one or more of C3.6 ketones or a mixture thereof with water, N- methylpyrrolidone, amides, halo-substituted C6-i 2 aromatic hydrocarbons propylene glycol, dimethyl sulfoxide, dimethyl carbonate, C alkyl alcohols, a mixture of a Ci -8 alkyl alcohol and water, acetonitriie or a mixture thereof with water, C2-6 alkyl acetates or their mixture with water, cellosolve, dimethyl carbonate, polyethylene glycol methyl ether and C2-8 ethers.
- the slurry as in step (a) may be prepared by heating to obtain the reaction mass followed by cooling.
- the reaction mass may be heated upto temperature of 40 to 60°C and the cooling temperature may be 5 to 10°C.
- the reaction mass may be stirred for 30 to 60 minutes.
- the isolation of substantially pure microcrystalline morioclinic form of asenapine maleate may involve filtration, removal of solvent under vaccum, drying under vaccum or any other techniques known in the art.
- the invention provides a process for preparing microcrystalline monoclinic form of asenapine maleate having (D95) less than about 10 microns, the process comprises
- step (d) isolating asenapine maleate with (D95) particle size less than about 30 microns; e) milling asenapine maleate obtained in step (d); and
- the reaction is preferably carried out in suitable solvent.
- the solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting acid addition salt.
- both Asenapine and the reactant acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures.
- a mixture, slurry, or solution of Asenapine and a solvent may be contacted with a reactant acid, or conversely, a mixture, slurry, or solution of reactant acid and a solvent may be contacted with Asenapine.
- both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for reactant acid may be identical with or different from the solvent system used for the asenapine.
- the solvent system can be comprised of a single solvent or a mixture of solvents.
- a two phase reaction scheme may be used wherein the asenapine and reactant acid are primarily reacted in one phase and the resulting asenapine salt of formula (II) compound is primarily present in the other phase due to, inter alia, solubility differences, etc.
- the temperature of contact of asenapine and reactant acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. slurry or two-phase solutions are also possible, though a single solution is generally preferred.
- the solvent for step (i) is selected from group consisting of C 3-6 ketone or a mixture thereof with water, N-methylpyrrolidone, C 3 _6 amides, halo-substituted C 6 - i 2 aromatic hydrocarbons propylene glycol, dimethyl sulfoxide, dimethyl carbonate, C alkyl alcohols such as methanol, ethanol, isopropanol, acetonitrile or a mixture thereof with water, C 2 -6 alkyl acetates or their mixture with water, cellosolve, dimethyl carbonate, polyethylene glycol methyl ether and C 2 . 8 ethers.
- step (i) The solution obtained in step (i) may be stirred for 30 to 60 minutes at temperature of 40°C to 60°C.
- the temperature of the reaction mass may be gradually cooled and stirred.
- step (i) may be stirred for 1 to 2 hours at 5°C to 10°C
- the sieving of asenapine maleate in step (iii) is performed through 200 mesh.
- the milling step to obtain microcrystalline monoclinic Asenapine Maleate in step (v) comprises of jet milling performed with feeding pressure of about 3 kg and grinding pressure of about 4 kg.
- the jet milling cycle may vary from 1 to 5 cycles to obtain (D95) less than about 10 microns.
- Another aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of microcrystalline Asenapine Maleate in monoclinic form having particle size, in terms of d95, is less than 10 microns, a pharmaceutically acceptable excipient.
- composition can be an immediate release dosage form or an extended release dosage form or buccal or sublingual or injectable or embraces tablets as well as pellets/beads/spheroids or other encapsulated forms.
- the compound can be in isolated and/or purified form, but such is not required.
- the compound includes various physical forms of the salt including dissolved forms, oil or liquid forms, and solid forms including amorphous and crystalline forms.
- the invention encompasses a pharmaceutical composition comprising crystalline Asenapine Maleate monoclinic form and at least one pharmaceutically acceptable excipient.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an effective amount of Asenapine Maleate in monoclinic form having particle size, in terms of d95, is less than 100 microns and a pharmaceutically acceptable excipient.
- Another embodiment of the invention encompasses the use of crystalline Asenapine Maleate monoclinic form having particle size, in terms of d95, is less than 100 microns for the manufacture of a medicament for the treatment of schizophrenia and acute mania associated with bipolar disorder.
- compositions comprising Asenapine salts of the invention.
- pharmaceutical compositions or “pharmaceutical formulations” includes tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
- compositions containing the asenapine maleate of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
- diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
- modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
- Another aspect of the present invention relates to the process for preparing amorphous form of asenapine maleate.
- reaction of asenapine maleate is preferably carried out in organic solvent or in mixture with water.
- Another embodiment of the invention encompasses a process for preparing amorphous asenapine maleate comprising slurrying asenapine maleate in a solvent selected from a group consisting of organic solvent such as aromatic hydrocarbons, glycerol, tetrahydrofuran, esters, ethers, ketones, alcohols and water or a mixture thereof.
- a process for preparing amorphous asenapine maleate comprising spray drying a solution of asenapine maleate in alcoholic solvent.
- Amorphous asenapine maleate can be isolated or recovered from the salt forming reaction by any convenient means.
- the amorphous Asenapine Maleate can be precipitated out of a solution or reaction mixture.
- the precipitation may be spontaneous depending upon the solvent system used and the conditions.
- the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated.
- a process for preparation an amorphous form of asenapine maleate which includes one or more of the following steps:
- Step a) invovles providing a solution of asenapine maleate in a solvent or mixture of solvent.
- the solution for step a) can be obtained by the known methods that include: (i) direct use of a reaction mixture containing asenapine maleate that is obtained in the course of its synthesis; or
- Suitable solvents that may be used in step a) include but are not limited to water; alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyi ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyi acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile, and polar apro
- Step b) involves isolation of an amorphous form of asenapine maleate from the solution of step a).
- the isolation may be affected by removing solvent.
- Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi otavapor, spray drying, agitated thin film dyring ("ATFD”), freeze drying (lyophilization), and the like or any other suitable technique.
- isolation can be effected by addition of suitable antisolvent to the solution obtain in step a), optionally by concentrating the solution obtained in step a).
- suitable anti-solvents that may be used can be selected from hydrocarbons like hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane and the like; aromatic hydrocarbons like toluene, xylene, chlorobenzene, ethylbenzene and the like; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol and the like.
- the process for preparing amorphous asenapine maleate may further comprise a recovery process.
- the recovery of amorphous asenapine maleate may be done by a method that doesn't include a drying step. Such method includes, but is not limited to, filtering the suspension.
- amorphous asenapine maleate may be prepared by a process comprising spray drying a solution of asenapine maleate in methanol.
- spray drying consists of bringing together a highly dispersed liquid and a sufficient volume of hot gas to produce evaporation and drying of the liquid droplets.
- a typical spray-drying apparatus includes a drying chamber, atomizing means for atomizing a solvent- containing feed into the drying chamber, a source of heated drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed and product collection means located downstream of the drying chamber. Examples of such apparatus include Niro Models PSD- 1 , PSD-2 and PSD-4 (Niro A/S, Soeborg, Denmark).
- the solution is prepared by dissolving asenapine maleate in methanol.
- the solution is spray-dried at an inlet temperature of from about room temperature to about 200° C, more preferably of about 60° C to about 120°C.
- the solution is spray-dried at an outlet temperature of from about room temperature to about 120°C, more preferably of about 37° C to about 75°C.
- asenapine salt can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of asenapine salt.
- an amorphous solid form of the asenapine salt compound can be recovered by spray drying or freeze drying or agitated thin film drying a solution containing the asenapine salt compound.
- the invention encompasses a pharmaceutical composition comprising amorphous asenapine maleate and at least one pharmaceutically acceptable excipient.
- One embodiment of the invention encompasses a pharmaceutical composition comprising amorphous asenapine maleate made by the processes of the invention, and at least one pharmaceutically acceptable excipient.
- Yet another embodiment of the invention encompasses a process for preparing a pharmaceutical composition of asenapine maleate comprising combining amorphous asenapine maleate with at least one pharmaceutically acceptable excipient.
- Another embodiment of the invention encompasses the use of amorphous asenapine maleate for the manufacture of a medicament for the treatment of schizophrenia and acute mania associated with bipolar disorder.
- Another embodiment of the invention encompasses the use of amorphous asenapine maleate made by the processes of the invention for the manufacture of a pharmaceutical composition.
- the obtained asenapine maleate was further treated with 200 ml of acetonitrile followed by treatment with 200 ml of ethanol and stirred for 30 minutes.
- the reaction mass was cooled to 5°C to 10°C and stirred for 2 hours.
- the product was filtered and washed with 50 ml of ethanol and further treated with 400 ml of ethanol at 25°C to 35°C and heated to 65°C to 70°C.
- the product was filtered and washed with ethanol.
- the reaction temperature was cooled to 50-55°C, further cooled to 20-25°C and stirred for 1 hour.
- the reaction temperature was cooled to 5°C to 10°C and stirred for 2 hours.
- the product was washed with 50 ml of chilled ethanol to afford monoclinic form of asenapine maleate.
- the obtained asenapine maleate monoclinic form was sieved through 200 mesh resulted with (D95) less than about 30 microns.
- 100 g of monoclinic asenapine maleate (polymorphic purity 99.5%) having particle size (D95) less than 5 microns obtained by micronization was treated with 100 ml of ethanol at 25°C to 35°C and heated to 65°C to 70°C. The product was filtered and washed with ethanol. The reaction temperature was cooled to 50-55°C, further cooled to 20-25°C and stirred for 1 hour. The reaction temperature was cooled to 5°C to 10°C and stirred for 2 hours. The product was washed with 50 ml of chilled ethanol to afford substantially pure microcrystalline monoclinic form of asenapine maleate.
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Abstract
La présente invention concerne une forme monoclinique sensiblement pure de maléate d'asénapine présentant une taille de particules d95 inférieure à environ 100 microns.
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Cited By (10)
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WO2012156677A1 (fr) * | 2011-05-18 | 2012-11-22 | Laboratorios Lesvi S.L. | Forme monoclinique micronisée stable de maléate d'asénapine et sa synthèse |
WO2012156676A1 (fr) * | 2011-05-18 | 2012-11-22 | Laboratorios Lesvi S.L. | Forme cristalline monoclinique de maléate d'asénapine présentant une granulométrie spécifique |
CN103772402A (zh) * | 2014-01-07 | 2014-05-07 | 万特制药(海南)有限公司 | 一种新的阿塞那平马来酸盐粗品精制方法 |
CN104447771A (zh) * | 2013-09-12 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | 一种稳定的马来酸阿塞那平化合物 |
KR20150036477A (ko) * | 2012-07-26 | 2015-04-07 | 히사미쓰 세이야꾸 가부시키가이샤 | 첩부제 및 그 제조 방법 |
US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
US11154510B2 (en) | 2015-06-11 | 2021-10-26 | Alrise Biosystems Gmbh | Process for the preparation of drug loaded microparticles |
US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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WO2012156676A1 (fr) * | 2011-05-18 | 2012-11-22 | Laboratorios Lesvi S.L. | Forme cristalline monoclinique de maléate d'asénapine présentant une granulométrie spécifique |
US9505771B2 (en) | 2011-05-18 | 2016-11-29 | Laboratories Lesvi S.L. | Stable micronised monoclin form of asenapine maleate and its synthesis |
US9533994B2 (en) | 2011-05-18 | 2017-01-03 | Laboratorios Lesvi S.L. | Monoclinic crystalline form of asenapine maleate with a specific particle size distribution |
WO2012156677A1 (fr) * | 2011-05-18 | 2012-11-22 | Laboratorios Lesvi S.L. | Forme monoclinique micronisée stable de maléate d'asénapine et sa synthèse |
KR20150036477A (ko) * | 2012-07-26 | 2015-04-07 | 히사미쓰 세이야꾸 가부시키가이샤 | 첩부제 및 그 제조 방법 |
KR102013476B1 (ko) | 2012-07-26 | 2019-08-22 | 히사미쓰 세이야꾸 가부시키가이샤 | 첩부제 및 그 제조 방법 |
CN104447771A (zh) * | 2013-09-12 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | 一种稳定的马来酸阿塞那平化合物 |
CN103772402A (zh) * | 2014-01-07 | 2014-05-07 | 万特制药(海南)有限公司 | 一种新的阿塞那平马来酸盐粗品精制方法 |
US11154510B2 (en) | 2015-06-11 | 2021-10-26 | Alrise Biosystems Gmbh | Process for the preparation of drug loaded microparticles |
US11931466B2 (en) | 2015-06-11 | 2024-03-19 | Ferring B.V. | Process for the preparation of drug loaded microparticles |
US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
US10980753B2 (en) | 2016-12-20 | 2021-04-20 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
US12138353B2 (en) | 2016-12-20 | 2024-11-12 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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